Atherosclerotic cardiovascular disease is the most common cause of death in the United States. Many natural compounds show promise to remedy this serious illness, but their low level of bioavailability and target specificity in the bdy makes administering them in therapeutic doses unrealistic. This is particularly true for (-)- epigallocatechin gallate (EGCG), a natural compound found in green tea, that is valuable for the prevention and treatment of atherosclerosis. The purpose of this project is to synthesize EGCG encapsulated chitosan-coated nanostructured lipid carriers (CSNLC-EGCG) to increase its level of stability, cellular bioavailability and targeting to aortic intimal macrophages, with the goal o preventing and reversing atherosclerotic lesion development. Aortic intimal macrophages are major cells responsible for atherosclerotic lesion development. These macrophages take up cholesterol-rich low- density lipoprotein (LDL), leading to the formation of cholesterol-laden macrophages (foam cells), which characterize early atherosclerotic lesions. EGCG can decrease cholesterol accumulation in aortic macrophages, inhibit foam cell formation, and reduce inflammatory factor release from aortic macrophages. These actions inhibit atherosclerotic lesion development and may promote regression of atherosclerotic lesions. Low levels of EGCG stability, bioavailability, and target specificity prevent these benefits from being fully realized. There is a critical need for engineered EGCG carriers to enhance its stability, cellular bioavailability and target specificity. We have previously encapsulated EGCG into CSNLC carrying an oxidized LDL-derived ligand. This ligand has a high binding affinity to a macrophage scavenger receptor CD36 and should therefore participate in the receptor mediated recognition and uptake of CSNLC into aortic intimal macrophages. The novelty of this research is to encapsulate EGCG into biodegradable and biocompatible CSNLC, with the aims of 1) targeting to aortic intimal macrophages through surface modification using a target ligand;and 2) preventing and reversing the development of atherosclerosis in genetically susceptible LDL receptor null mice. To determine the specificity with which CSNLC-EGCG targets aortic intimal macrophages, cellular binding assay, cellular uptake of EGCG and oxidized LDL and inflammatory factor secretion levels will be measured in human macrophages derived from THP-1 monocytes. To determine the effects of CSNLC-EGCG on atherosclerosis in vivo, LDL receptor null mice will receive an atherogenic diet for 20 weeks. One experimental group will receive CSNLC-EGCG from week 1 until sacrifice, so that effects on the development of atherosclerosis can be observed. A second experimental group will receive CSNLC-EGCG from week 10 through week 20 so that effects on established atherosclerosis can be observed. A pathologist will evaluate the safety of EGCG and CSNLC in mice. This innovation portends a potential breakthrough in the prevention and treatment of atherosclerosis by using natural compounds with minimized immunogenicity and side-effects. The long-term goal of this line of research is to use biodegradable and biocompatible nanoparticles to increase bioavailability, solubility, stability and payload of therapeutic nutrients and natural compounds, lower their toxicity, prolong their circulation time, and target them to specific cells or tissues for disease prevention, diagnosis and treatment. PUBLIC HEALTH RELEVANCE: The proposed research will provide new insights and advance knowledge on nutraceuticals and chronic diseases, and have a wide range of potential applications in biomedical and health science. Attainment of enhanced stability, bioavailability and targeting through encapsulation of (-)-epigallocatechin gallate (EGCG) into biocompatible and biodegradable nanocarriers will open a new field in disease prevention and therapy of using natural compounds, representing a huge commercial market in the U.S. and abroad. The outcome is also expected to produce dramatic savings in the cost of medical care and improve the quality of life.